14-hydroxyequilenin and derivatives



Patented Aug. 31, 1 954 UNITED STATES PATENT OFFICE 14-HYDROXYEQUILENIN AND DERIVATIVES Neal L. McNiven, Shrewsbury, Mass., assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application May 1 1, 1953, Serial No. 354,404

3 Claims. (Cl. 260397.45)

l 2 This invention relates to oxidation products coholic medium with a basic reagent such as of equilenin and to processes for the preparation potash, caustic soda, potassium carbonate, or the thereof. In particular, this invention relates to like. hydroxy derivatives of equilenin having the for- Among the compounds of the preesnt invention which may be obtained by the foregoing O procedure are 14-hydroxyequilenin acetate, hav- Hso ing the formula O I I OH p mula wherein A is selected from the group consisting of hydrogen, and lower alkyl and lower alkanoyl radicals. Lower alkyl and lower alkanoyl radicals il in methyl ether, having the are defined as those containing not more than 4 formu1a carbon atoms, and include methyl, ethyl, propyl, I OH isopropyl, butyl, isobutyl, secondary butyl, formyl, acetyl, propionyl, butyryl, and isobutyryl radicals.

The compounds of this invention are useful chemotherapeutic materials in the field of cardiac pathology. In particular, they are valuable because of their digitalis-like activity, showing marked capacity for myocardial stimulation in 0H instances of insufiiciency associated with the fail- H3O ing heart.

The subject compounds are soluble in aqueous solutions of alcohols and other water-miscible and 14 hydroxyequllemnhavmg the formula organic solvents. They may be administered in H3O solid form as tablets or capsules; dissolved in aqueous media, they may be given parenterially.

The compounds to which this invention relates may be conveniently prepared according to the following procedure: An equilenin derivative- 0H wherein protection of the hydroxyl at C3 (and other substituent hydroxyls, if any) has been ei- HOT fected by esterification, etherification or the equiva1entis subjected to the action of an 40 The following examples will illustrate in detail oxidizing agent such as chromic anhydride in certain of the compounds comprehended by the aqueous acetic acid, tertiary butyl chromate, present invention and methods which have been chromic oxide in glacial acetic acid, chromyl devised for their preparation. However, the inchloride in carbon tetrachloride, potassium pervention is not to be construed as limited thereby, manganate in aqueous acetic acid, and the like; either in spirit or in scope, since it will be apand the neutral oxidation products thereby obparent to those skilled in the art of organic syntained are chromatographed to give the desired thesis that many modifications, both of materials hydroxy and hydroxyoxo equilenin ester or ether. and of methods, may be practiced without de- The reaction is ordinarily run at moderate temparting from the purpose and intent of this disperatures ranging from 10 to 55 centigrade for closure. In the examples hereinafter detailed, periods of time varying between 15 minutes and temperatures are given in degrees centigrade 4 hours. The 3-hydroxy derivatives may be con- C.), and relative amounts of materials in milveniently prepared from the corresponding 3- ligrams (mg), grams (gm.), milliliters (1111.) or esters by conventional hydrolytic techniques-as, liters (1.) except as otherwise noted. Specific r0- for example, by saponification in aqueous altations refer to chloroform solutions.

Example 1 To a solution of 4 gm. of d-equilenin acetate (derived from natural equilenin or by resolution and subsequent acetylation of d,l-equilenin) in 750 ml. of glacial acetic acid is added, with stirring at 20 C., a solution of 2.6 gm. chromic anhydride in 7.85 ml. water and 32 ml. glacial acetic acid. The reaction mixture is maintained at 20 C. for 1 hour with continued stirring, then poured into 2 l. of water and extracted with 10 50-ml. portions of methylene chloride. The combined extracts are washed with 135-ml. portions of a solution consisting of 24 m1. of saturated aque ous sodium carbonate, 34 ml. of saturated aqueous sodium bicarbonate, and 77 ml. of water, then dried over anhydrous sodium sulfate. The solvent is next removed by vacuum distillation at a maximum bath temperature of 55 C., leaving a gummy residue which contains the neutral oxidation products. The residue is taken up in 200 ml. of benzene, and this solution is chromatographed on 110 gm. of 100-200 mesh silica gel. The adsorbed material is eluted successively with 50-ml. portions of mixtures of benzene and ethyl acetate containing gradually increasing amounts of ethyl acetate. Following evaporation of these eluates to dryness, the individual weights of residues thus obtained are plotted against the cumulative eluate volume. Three peaks result.

A. Recovery of starting material.-Material.

represented by the first peak is unchanged dequilenin acetate.

B. 14 hydrorycquilenin acetate. Material represented by that portion of the second peak lying to the right of a line drawn perpendicularly through its summit is crystalized from methyl alcohol to give a product, M. P. 178-1795 C., [a] |-105", the infrared absorption spectrum of which contains the characteristic bands of an alcoholic hydroxyl group. The product is l4-hydroxyequilenin acetate.

C. Hydrorcy-il-oztoequilenin acetate.-Material represented by the third peak of the chromatogram of the oxidation products of d-equilenin acetate is crystallized from methyl alcohol to give a substance, M. P. 235-237 C., [a] +288. Infrared absorption spectra display the characteristic bands of a conjugated keto group and of an alcoholic hydroxyl group. This material is hydroxy-ll-oxo-equilenin acetate.

Example 2 d,l-14-hydroxyeqailenin methyl ether.-A 680 mg. sample of d,l-equilenin methyl ether, oxidized according to the procedure of Example 1 using chromic anhydride in aqueous acetic acid solution, and chromatographed on silica gel as before, gives a characteristic 3-peak chromatogram. Material represented by the latter half of the second peak-upon treatment in methyl alcohol solution with decolorizing charcoal, and crys tallization of this alcoholic solution-gives d,l-l4- hydroxyequilenin methyl ether, M. P. 164-1655 C. The infrared absorption spectrum contains the characteristic band of an alcoholic hydroxvl group.

I claim:

1. I-Iydroxy derivatives of equilenin having the formula wherein A is selected from the group consisting of hydrogen, lower alkyl and lower alkanoyl radicals.

2. l l-hydroxyequilenin acetate.

3. l l-hydroxyequilenin methyl ether.

No references cited. 

1. HYDROXY DERIVATIVES OF EQUILENIN HAVING THE FORMULA 